Flavonoids are ubiquitous secondary metabolites in plants with many known health benefits, which are mostly ascribed to their potent anti-oxidant activity. However, a search for novel nicotinic ligands, using high throughput pharmacological screening of a native plant extract library, and subsequently a pure flavonoid library, led to the highly surprising conclusion that some methoxylated quercetin-like flavonoid derivatives have partial agonist activity, selectively at the alpha7-subtype of nicotinic receptor for acetylcholine (nicAChR). Activation of these receptors on microglia and macrophages is known to reduce the release of inflammatory mediators by these cells, thereby reducing chronic inflammation in the CNS and peripheral tissues. Since there is a wealth of evidence which implicates chronic inflammatory changes in the neurodegeneration and organ damage associated with alcoholism, this implies that these specific flavonoids are of potential value for these therapeutic targets. The same flavonoids have added value, specifically for alcoholism, in that they retain potent anti-oxidant activity, and so should also protect tissues against the oxidative stress induced by alcohol metabolism. This phase 1 proposal is to investigate the effects of alpha7-nicAChR active flavonoids on bacterial toxin-induced release of inflammatory mediators from microglia and macrophages. The role of alpha7-nicAChRs in any effects seen will be evaluated using selective agonists and antagonists at these receptors. The objective is to identify agents with therapeutic potential, which will be evaluated in more complex models of alcohol-induced tissue damage in vitro and in vivo in phase 2. It is important to note that although the most active flavonoids were discovered in native plants, some of the alpha7-nicAChR active flavonoids in the library are present in common crop plants such as apples and onions. This makes regulatory approval for these flavonoids as nutraceuticals or functional foods relatively easy to obtain, and limited toxicity testing in phase 2 will be followed by commercialization with a major global food company which has already indicated strong interest in the anti-inflammatory properties of these natural products. PUBLIC HEALTH RELEVANCE: Alcoholism (either dependence or abuse) affects more than 8% of the population of the US, and the societal costs approach $200BN annually. About half of this sum is medical cost, much of which is accrued in treating alcohol-related organ damage. This organ damage is commonly associated with cellular inflammation, and this is also a major contributing factor to alcohol-induced neurodegeneration, which may rival Alzheimer's dementia in its prevalence in the US. Despite this, there are currently no accepted approaches to preventing or reversing this tissue damage. This application proposes a novel approach to organ and brain damage which has major implications for pharmacotherapy of, and/or nutritional intervention in, these therapeutic targets.